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The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts.
Basic Res Cardiol. 2003 Sep; 98(5):319-28.BR

Abstract

OBJECTIVE

Nitric oxide (NO) is known to act as a mediator of tissue injury as well as being a potent endogenous vasodilator. The functional and metabolic effects of NO on ischemia-reperfusion injury are still controversial. The aim of this study was to clarify the relationship between the degree of NO synthase (NOS) inhibition and the effects on ischemia-reperfusion injury.

METHODS AND RESULTS

Langendorff-perfused rat hearts were subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. The recovery of left ventricular developed pressure (LVDP), creatine kinase (CK) release, and myocardial high energy phosphates were measured in hearts perfused with or without NOS inhibitors, L-N(G)-monomethyl arginine (L-NMMA) or N(G)nitro-L-arginine methylester (L-NAME). NOS inhibitors exerted different effects on the recovery of LVDP and CK release depending on the concentration. The low dose of L-NMMA improved the recovery of LVDP, decreased the CK release during reperfusion, and preserved the myocardial adenosine triphosphate content after reperfusion. In contrast, the high dose of L-NMMA had adverse effects. L-NMMA reduced NO release in coronary effluent in a dose-dependent fashion. Both effects of L-NMMA were abolished by excessive co-administration of L-arginine and the same doses of D-N(G)-monomethyl arginine (D-NMMA) showed no effect on ischemia-reperfusion injury. Therefore, both effects were due to NOS inhibition. In addition, L-NMMA suppressed the myocardial malondialdehyde accumulation, an indicator of oxidative stress, which might be attributed to the beneficial effects by partial NOS inhibition. On the other hand, the high dose L-NMMA significantly decreased coronary fl ow during aerobic perfusion and reperfusion. Therefore, it is conceivable that the vasoactive NOS inhibition contributes to the harmful effects, which might exceed the beneficial effects due to a decrease in oxidative stress.

CONCLUSION

The present results showed that NO inhibitors had dual effects on mechanical function and energy metabolism depending on the concentration. Non-vasoactive inhibition of NOS had beneficial effects due to the suppression of oxidative injury. However, strong vasoactive inhibition of NOS exacerbated the ischemia-reperfusion injury.

Authors+Show Affiliations

Second Dept. of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12955405

Citation

Kobara, Miyuki, et al. "The Dual Effects of Nitric Oxide Synthase Inhibitors On Ischemia-reperfusion Injury in Rat Hearts." Basic Research in Cardiology, vol. 98, no. 5, 2003, pp. 319-28.
Kobara M, Tatsumi T, Takeda M, et al. The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts. Basic Res Cardiol. 2003;98(5):319-28.
Kobara, M., Tatsumi, T., Takeda, M., Mano, A., Yamanaka, S., Shiraishi, J., Keira, N., Matoba, S., Asayama, J., & Nakagawa, M. (2003). The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts. Basic Research in Cardiology, 98(5), 319-28.
Kobara M, et al. The Dual Effects of Nitric Oxide Synthase Inhibitors On Ischemia-reperfusion Injury in Rat Hearts. Basic Res Cardiol. 2003;98(5):319-28. PubMed PMID: 12955405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts. AU - Kobara,Miyuki, AU - Tatsumi,Tetsuya, AU - Takeda,Mitsuo, AU - Mano,Akiko, AU - Yamanaka,Satoshi, AU - Shiraishi,Jun, AU - Keira,Natsuya, AU - Matoba,Satoaki, AU - Asayama,Jun, AU - Nakagawa,Masao, Y1 - 2003/06/20/ PY - 2002/12/16/received PY - 2003/04/17/revised PY - 2003/05/12/accepted PY - 2003/9/5/pubmed PY - 2004/6/2/medline PY - 2003/9/5/entrez SP - 319 EP - 28 JF - Basic research in cardiology JO - Basic Res. Cardiol. VL - 98 IS - 5 N2 - OBJECTIVE: Nitric oxide (NO) is known to act as a mediator of tissue injury as well as being a potent endogenous vasodilator. The functional and metabolic effects of NO on ischemia-reperfusion injury are still controversial. The aim of this study was to clarify the relationship between the degree of NO synthase (NOS) inhibition and the effects on ischemia-reperfusion injury. METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. The recovery of left ventricular developed pressure (LVDP), creatine kinase (CK) release, and myocardial high energy phosphates were measured in hearts perfused with or without NOS inhibitors, L-N(G)-monomethyl arginine (L-NMMA) or N(G)nitro-L-arginine methylester (L-NAME). NOS inhibitors exerted different effects on the recovery of LVDP and CK release depending on the concentration. The low dose of L-NMMA improved the recovery of LVDP, decreased the CK release during reperfusion, and preserved the myocardial adenosine triphosphate content after reperfusion. In contrast, the high dose of L-NMMA had adverse effects. L-NMMA reduced NO release in coronary effluent in a dose-dependent fashion. Both effects of L-NMMA were abolished by excessive co-administration of L-arginine and the same doses of D-N(G)-monomethyl arginine (D-NMMA) showed no effect on ischemia-reperfusion injury. Therefore, both effects were due to NOS inhibition. In addition, L-NMMA suppressed the myocardial malondialdehyde accumulation, an indicator of oxidative stress, which might be attributed to the beneficial effects by partial NOS inhibition. On the other hand, the high dose L-NMMA significantly decreased coronary fl ow during aerobic perfusion and reperfusion. Therefore, it is conceivable that the vasoactive NOS inhibition contributes to the harmful effects, which might exceed the beneficial effects due to a decrease in oxidative stress. CONCLUSION: The present results showed that NO inhibitors had dual effects on mechanical function and energy metabolism depending on the concentration. Non-vasoactive inhibition of NOS had beneficial effects due to the suppression of oxidative injury. However, strong vasoactive inhibition of NOS exacerbated the ischemia-reperfusion injury. SN - 0300-8428 UR - https://www.unboundmedicine.com/medline/citation/12955405/The_dual_effects_of_nitric_oxide_synthase_inhibitors_on_ischemia_reperfusion_injury_in_rat_hearts_ L2 - https://dx.doi.org/10.1007/s00395-003-0423-x DB - PRIME DP - Unbound Medicine ER -